The present invention provides an improved process for making [3-[α-(dimethylamino)ethyl]phenyl]-N-methylethylcarbamate, a useful pharmaceutically active agent.
Rivastigmine is a generic name for the compound (S)-[3-[α-(Dimethylamino)-ethyl]phenyl]-N-methylethylcarbamate of the formula (Ib):

More generally, rivastigmine is the (S)-enantiomer of a compound of general formula (I), wherein the dotted line indicates that this carbon-carbon bond is attached to the asymmetric carbon and the compound of formula (I) may exist as a racemate or as an enantiomer.

Rivastigmine (Ib) is a pharmaceutically active compound that acts as a reversible, brain-selective acetylcholinesterase inhibitor. In existing medicinal products, it is marketed as a salt with L-tartaric acid-rivastigmine hydrogentartrate. Rivastigmine hydrogentartrate is indicated for the symptomatic treatment of mild to moderately severe Alzheimer disease.
The compound of formula (I) has been disclosed in EPB 193,926 and the U.S. Pat. No. 4,948,807. Rivastigmine hydrogentartrate was specifically disclosed in U.S. Pat. No. 5,602,176.
The compound of formula (I) is a phenylcarbamate, i.e., its molecule is formed by a phenolic moiety A linked by a carbonyl bridge C to an aminic moiety B as shown in the schematic figure below:

Accordingly, the known processes for making compounds of formula (I), including rivastigmine, generally employ the aminophenol compound (II) and ethylmethylamine (III) as starting materials:
with various ways of constructing the carbonyl linking bridge.
As in the compound (I), the compound (II) has one asymmetric carbon (illustrated by the dotted line in the figure (II)) and may be employed in the synthesis of rivastigmine as the racemate (IIa) or as a single enantiomer, preferably the S-enantiomer (IIb).

In the first case, racemic compound (I-R) is produced, which can be resolved into its enantiomers to yield rivastigmine. In the latter case, rivastigmine is produced directly. The compound (IIb) is generally obtainable by the resolution of the compound (IIa) into enantiomers. Schematically, the whole process may be depicted as follows:

The original process employed the racemic compound (IIa), yielding the racemate (I-R). The resolution of the (I-R) into enantiomers as well as the isolation of the (S)-enantiomer as a hydrogentartrate salt has been disclosed in GB 2203040.
This process has been improved in WO 2004-037771, wherein it was found that the racemic (IIa) may be replaced by the enantiomerically pure compound, particularly the (S)-enantiomer (IIb). No racemization occurs during the subsequent bridge-forming reaction and the desired rivastigmine (Ib) may thus be prepared without the resolution in the last step. A similar process has been disclosed in CN 1486973.
Two general synthetic concepts are known for building up the bridge (C) between the compounds (II) and (III) to form the desired carbamoyl ester.
The first concept is based on the activation of the amine (III) before the reaction with the phenol. The activated intermediate may be isolated and then it reacts with the aminophenol (II). In EPB 193926, the activated intermediate (the bridge-forming reagent) is a carbamoyl halide of the formula (IV):
which is formed by the reaction of compound (III) with a phosgene reagent. The condensation reaction with compound (II) needs an excess of this carcinogenic substance and requires the presence of sodium hydride as a base. In another possibility, the amine (III) may be converted into an isocyanate, which then reacts with compound (II).
In WO 03-101917, the bridge-forming reagent is a carbamoyl ester, particularly the p-nitro phenyl carbamate of the formula (V).
The reported advantage is that the use of compound (V) does not require the use of NaH for the condensation reaction with compound (II), allowing more common bases to be used. Another reported advantage is that the bridge-forming reagent (V) is less hazardous and more user-friendly. However, the reaction using compound (V) requires high temperatures and long reaction time (100° C., 35-40 hours). The carbamate (V) must be synthetized in an extra reaction step involving the ethylmethyl amine (III) and p-nitrophenylchloroformate (VI).

Conversely, the second concept is based on the activation of the phenol group in (II) by an activation agent; typically forming an intermediate of general formula (VII).
The intermediate (VII) is reacted with the amine (III), wherein L is a suitable leaving group, to form the compound (I). This concept was generally discussed in US 2005/0096387 for compounds similar to rivastigmine and was actually used for the synthesis of rivastigmine in WO 2006-048720, wherein the activation agent “of choice” is carbonyldiimidazole (VIII).

The reaction intermediate (VII) may be produced in situ and may react with the amine (III) without a need of its isolation, which is an advantage over the first concept. The reported reaction conditions for forming the intermediate (VII) by using carbonyldiimidazole (VIII) are disadvantageous (e.g., long reaction time and high temperatures).
WO 2006-048720 also provides for an alternative within this second concept, where the phenol activation agent may be p-nitrophenylchloroformate (VI); also mentioned above as an amine activation agent (see pg. 6, line 29-30, of WO 2006-048720). If one were to apply this activation agent to the corresponding phenol compound, it appears that the active intermediate (VII) could be represented as the compound (VII-1).

It has been discovered during the research leading to the present invention that the reaction conditions for activating the compound (II) with p-nitrophenylchloroformate (VI) are disadvantageous, including the need to use very low temperatures (e.g., less than −40° C.) in order to obtain the product with good yield and purity (see Comparative example 1 hereinafter).
Accordingly, there is a need to provide a simple process for making the compound of formula (I), particularly rivastigmine of the formula (Ib) and/or its racemic analogue (Ia), that can avoid extreme reagents and/or extreme conditions.